It has become abundantly clear that the phenomenon of senescence in cancer is a very complex one. While senescence of the tumor cell is a desired outcome for tumor therapy, senescence of normal fibroblasts in the microenvironment may promote progression of nearby tumor cells. In aging patients, an increasing percentage of skin fibroblasts become senescent, thus we are interested in the effects of the aging microenvironment on tumor progression. Older individuals who present with melanoma have a worse prognosis, and this could be due to factors such as decreased immunity, or changes in the microenvironment. Klotho is a gene that interacts with Wnts, and whose knockdown can lead to accelerated aging. We are studying the relationship between klotho and Wnt5A using melanoma as a model, and normal, aging skin. We are in the process of determining whether older skin fibroblasts have an increase in Wnt5a, and a loss of klotho. If this is so, we will ask if we can make melanoma cells more invasive if we co-culture them with old vs young fibroblasts. Further, we will knock klotho out of the younger fibroblasts, and see what effects that has on secretion of different factors from these fibroblasts, and if we can accelerate senescence, and if those senescing fibroblasts make melanoma cells more invasive. On a long term basis we will also ask if oncogene induced senescence can influence surrounding cells in a co-culture system- eg, skin fibroblasts, and make them senesce and in turn, release factors that then cause tumor cells to invade. Gene expression profiling studies will also be performed to obtain a global overview of thes studies.